Structure of Human Factor D

Narayana, S.V.L.; Carson, M.; El‐Kabbani, Ossama; Kilpatrick, J. Michael; Moore, Dwight; Chen, Xi; Bugg, Charles E.; Volanakis, John E.; DeLucas, Lawrence J.

doi:10.1006/jmbi.1994.1021

Cited by 86 publications

(55 citation statements)

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“…The respective active-site Ser195 and Aspl02 residues nearly overlap, while the His57 positions differ significantly. (The rationale for this difference has been discussed extensively in previous factor D papers : Cole et al, 1997;Narayana et al, 1994. ) In this first binding mode, the aromatic rings of the two inhibitor molecules are almost superposed, though it quickly becomes evident that the DCI:D binding site could not accommodate the 7-guanidino group (of the isocoumarin inhibitor) inside the S1 specificity pocket without breaking the Arg218-Asp189 salt bridge at the bottom of the specificity pocket of D. In trypsin, residue 218 is a glycine, which allows the long positively charged amino-acid side chains of the natural substrates direct access to Asp189.…”

Section: Comparison Of Dci:d With An Isocoumarin-trypsin Complexmentioning

confidence: 96%

“…Resulting from the low catalytic activity of D toward thioester substrates, others postulated that a conformational change in the active site of D may be induced by the substrate, the C3bB complex (Kam et al, 1987). The structure of native D has been solved to 2.0 A resolution (ldsu ;Narayana et aL, 1994), demonstrating that the protein exhibits the same general structural fold as the serine protease superfamily, yet the catalytic triad residues are not positioned in a manner conducive to efficient catalysis, revealing a 'zymogen-like' conformation of the native enzyme. At minimum, a conformational change that realigns these residues must occur to induce enzymatic activity.…”

Section: Introductionmentioning

confidence: 99%

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Structure of 3,4-Dichloroisocoumarin-Inhibited Factor D

Cole

Kilpatrick

Chu

et al. 1998

Acta Crystallogr D Biol Crystallogr

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Factor D (D) is a serine protease essential in the activation of the alternative complement pathway. Only a few of the common serine protease inhibitors inhibit D, binding covalently to the serine hydroxyl of the catalytic triad. 3,4-Dichloroisocoumarin (DCI) is a mechanism-based inhibitor which inhibits most serine proteases and many esterases, including D. The structure of the enzyme:inhibitor covalent adduct of D with DCI, DCI:D, to a resolution of 1.8 ,~ is described, which represents the first structural analysis of D with a mechanism-based inhibitor. The side chain of the ringopened DCI moiety of the protein adduct undergoes chemical modification in the buffered solution, resulting in the formation of an et-hydroxy acid moiety through the nucleophilic substitution of both CI atoms. The inhibited enzyme is similar in overall structure to the native enzyme, as well as to a variety of isocoumarininhibited trypsin and porcine pancreatic elastase (PPE) structures, yet notable differences are observed in the active site and binding mode of these small-molecule inhibitors. One region of the active site (residues 189-195) is relatively conserved between factor D, trypsin, and elastase with respect to amino-acid sequence and to conformation. Another region (residues 214-220) reflects the amino-acid substitutions and conformational flexibility between these enzymes. The carbonyl O atom of the DCI moiety was found to be oriented away from the oxyanion hole, which greatly contributes to the stability of the DCI:D adduct. The comparisons of the active sites between native factor D, DCl-inhibited factor D, and various inhibited trypsin and elastase (PPE) molecules are providing the chemical bases directing the design of novel, small-molecule pharmaceutical agents capable of modulating the alternative complement pathway. AbbreviationsD, factor D; B, factor B; DCI, 3,4-dichloroisocoumarin; DFP, diisopropyl fluorophosphate; DIP, diisopropyl t Current address:

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Section: Comparison Of Dci:d With An Isocoumarin-trypsin Complexmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Structure of 3,4-Dichloroisocoumarin-Inhibited Factor D

Cole

Kilpatrick

Chu

et al. 1998

Acta Crystallogr D Biol Crystallogr

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“…However, the detailed path of the substrate outside of the crucial P3-P1Ј region diverges among different members of the family, reflecting specific biological roles. For example, serine proteases involved in fibrinolysis (28), in blood coagulation (29), and in the complement system (30) are all members of the family possessing the chymotrypsin fold. These enzymes recognize specific cleavage sites and are themselves the targets of protein inhibitors, which play key roles in regulating these processes.…”

Section: Role Of Surface Loops In Determiningmentioning

confidence: 99%

Evolutionary Divergence of Substrate Specificity within the Chymotrypsin-like Serine Protease Fold

Perona

Craik

1997

Journal of Biological Chemistry

328

256

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“…A manual model built using techniques based on a presentation by Greer (1988) gave a preliminary solution of the crystal structure via molecular replacement. The crystallographic refinement of factor D to 2.0 A based on MIR data is described by Narayana et al (1994). Model phases were used only to locate heavy-atom sites.…”

Section: Modelsmentioning

confidence: 99%

Error detection in crystallographic models

Carson

Buckner²,

Yang³

et al. 1994

Acta Cryst D

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A variety of criteria were tested for identifying errors in protein crystal coordinates. Statistical analysis was based on comparisons of a highly refined crystal structure and several preliminary models derived from molecular replacement. A protocol employing temperature factors, real-space fit residuals, geometric strains, dihedral angles and shifts from the previous refinement cycle is developed. These results are generally applicable to the detection of errors in partially refined protein crystal structures.

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Structure of Human Factor D

Cited by 86 publications

References 0 publications

Structure of 3,4-Dichloroisocoumarin-Inhibited Factor D

Structure of 3,4-Dichloroisocoumarin-Inhibited Factor D

Evolutionary Divergence of Substrate Specificity within the Chymotrypsin-like Serine Protease Fold

Error detection in crystallographic models

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